tbuckley/cabot-search huggingface dataset:
Prospective validation of a biomarker-driven response prediction model to romiplostim in lower-risk myelodysplastic neoplasms – results of the EUROPE trial by EMSCO
Authors: Anne Sophie Kubasch, Aristoteles Giagounidis, Georgia Metzgeroth, Anna Jonasova, Regina Herbst, Jose Miguel Torregrosa Diaz, Benoit De Renzis, Katharina S. Götze, Marie-Luise Huetter-Kroenke, Marie-Pierre Gourin, Borhane Slama, Sophie Dimicoli-Salazar, Pascale Cony-Makhoul, Kamel Laribi, Sophie Park, Katja Jersemann, Dorothea Schipp, Klaus H. Metzeler, Oliver Tiebel, Katja Sockel, Silke Gloaguen, Anna Mies, Fatiha Chermat, Christian Thiede, Rosa Sapena, Richard F. Schlenk, Pierre Fenaux, Uwe Platzbecker, Lionel Adès
Journal: Leukemia (2022)

The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the 'European Myelodysplastic Neoplasms Cooperative Group' (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response.
A Water‐Soluble Quercetin Conjugate with Triple Targeting Exerts Neuron‐Protective Effect on Cerebral Ischemia by Mitophagy Activation
Authors: Juan Cen, Runfang Zhang, Tingkui Zhao, Xin Zhang, Chuan Zhang, Jie Cui, Keqing Zhao, Shaofeng Duan, Yuqi Guo
Journal: Advanced Healthcare Materials (2022)

The existing treatments for ischemic stroke cannot meet the clinical needs so far. Quercetin (QT) is an effective apoptosis inhibitor and antioxidant flavonoid, but its water solubility is poor and has no targeting. In this study, QT is modified with hyaluronic acid (HA) to form a water-soluble conjugate HA-QT, which can specifically bind to CD44 receptors and response to hyaluronidase. Next, a novel delivery system SS31-HA-QT is prepared by further modification with SS31, a polypeptide capable of penetrating the blood-brain barrier (BBB) and indiscriminately targeting mitochondria. Meanwhile, IR780, a near-infrared dye, is conjugated onto HA-QT and SS31-HA-QT to form diagnosis tools to trace HA-QT and SS31-HA-QT. In vitro and in vivo results shows that SS31 can four-fold increase the drug penetration into BBB without any toxicity. The highly expressed CD44 and hyaluronidase in ischemic area ensured the targeted delivery of QT to the ischemic region. Importantly, the mitochondrial targeting of damaged neurons is also achieved by SS31. Further studies confirmed that SS31-HA-QT exerted neuron-protection by activating mitophagy, and its mechanism involved Akt/mTOR related TFEB and HIF-1α activation. Hence, SS31-HA-QT shall be a promising neuroprotective drug due to its high water-solubility, superior triple-targeted neuroprotective ability, low toxicity, and high efficiency.
The miR-181 family regulates colonic inflammation through its activity in the intestinal epithelium
Authors: Monica T. Jimenez, Megan L. Clark, Jasmine M. Wright, Michaël F. Michieletto, Suying Liu, Isabel Erickson, Lenka Dohnalova, Giulia T. Uhr, John Tello-Cajiao, Leonel Joannas, Adam Williams, Nicola Gagliani, Meenakshi Bewtra, Vesselin T. Tomov, Christoph A. Thaiss, Jorge Henao-Mejia
Journal: The Journal of Experimental Medicine (2022)

The intestinal epithelium is a key physical interface that integrates dietary and microbial signals to regulate nutrient uptake and mucosal immune cell function. The transcriptional programs that regulate intestinal epithelial cell (IEC) quiescence, proliferation, and differentiation have been well characterized. However, how gene expression networks critical for IECs are posttranscriptionally regulated during homeostasis or inflammatory disease remains poorly understood. Herein, we show that a conserved family of microRNAs, miR-181, is significantly downregulated in IECs from patients with inflammatory bowel disease and mice with chemical-induced colitis. Strikingly, we showed that miR-181 expression within IECs, but not the hematopoietic system, is required for protection against severe colonic inflammation in response to epithelial injury in mice. Mechanistically, we showed that miR-181 expression increases the proliferative capacity of IECs, likely through the regulation of Wnt signaling, independently of the gut microbiota composition. As epithelial reconstitution is crucial to restore intestinal homeostasis after injury, the miR-181 family represents a potential therapeutic target against severe intestinal inflammation.
Structural factors associated with SARS-CoV-2 infection risk in an urban slum setting in Salvador, Brazil: A cross-sectional survey
Authors: Mariam O. Fofana, Nivison Nery, Juan P. Aguilar Ticona, Emilia M. M. de Andrade Belitardo, Renato Victoriano, Rôsangela O. Anjos, Moyra M. Portilho, Mayara C. de Santana, Laiara L. dos Santos, Daiana de Oliveira, Jaqueline S. Cruz, M. Catherine Muenker, Ricardo Khouri, Elsio A. Wunder, Matt D. T. Hitchings, Olatunji Johnson, Mitermayer G. Reis, Guilherme S. Ribeiro, Derek A. T. Cummings, Federico Costa, Albert I. Ko
Journal: PLoS Medicine (2022)

The structural environment of urban slums, including physical, demographic, and socioeconomic attributes, renders inhabitants more vulnerable to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Yet, little is known about the specific determinants that contribute to high transmission within these communities. We therefore aimed to investigate SARS-CoV-2 seroprevalence in an urban slum in Brazil.
Myelodysplastic syndromes with del(5q): A real-life study of determinants of long-term outcomes and response to lenalidomide
Authors: Carmelo Gurnari, Alfonso Piciocchi, Stefano Soddu, Fabrizio Bonanni, Emilia Scalzulli, Pasquale Niscola, Ambra Di Veroli, Anna Lina Piccioni, Monica Piedimonte, Gianluca Maiorana, Prassede Salutari, Laura Cicconi, Michelina Santopietro, Svitlana Gumenyuk, Chiara Sarlo, Susanna Fenu, Agostino Tafuri, Roberto Latagliata, Luana Fianchi, Marianna Criscuolo, Jaroslaw P. Maciejewski, Luca Maurillo, Francesco Buccisano, Massimo Breccia, Maria Teresa Voso
Journal: Blood Cancer Journal (2022)
Targeting RNA N6-methyladenosine modification: a precise weapon in overcoming tumor immune escape
Authors: Wei Li, Yi Hao, Xingda Zhang, Shouping Xu, Da Pang
Journal: Molecular Cancer (2022)

Immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized the treatment of many types of cancer, particularly advanced-stage cancers. Nevertheless, although a subset of patients experiences dramatic and long-term disease regression in response to ICIs, most patients do not benefit from these treatments. Some may even experience cancer progression. Immune escape by tumor cells may be a key reason for this low response rate. N6-methyladenosine (m6A) is the most common type of RNA methylation and has been recognized as a critical regulator of tumors and the immune system. Therefore, m6A modification and related regulators are promising targets for improving the efficacy of tumor immunotherapy. However, the association between m6A modification and tumor immune escape (TIE) has not been comprehensively summarized. Therefore, this review summarizes the existing knowledge regarding m6A modifications involved in TIE and their potential mechanisms of action. Moreover, we provide an overview of currently available agents targeting m6A regulators that have been tested for their elevated effects on TIE. This review establishes the association between m6A modifications and TIE and provides new insights and strategies for maximizing the efficacy of immunotherapy by specifically targeting m6A modifications involved in TIE.
Abnormal molecular signatures of inflammation, energy metabolism, and vesicle biology in human Huntington disease peripheral tissues
Authors: Andreas Neueder, Kerstin Kojer, Tanja Hering, Daniel J. Lavery, Jian Chen, Nathalie Birth, Jaqueline Hallitsch, Sonja Trautmann, Jennifer Parker, Michael Flower, Huma Sethi, Salman Haider, Jong-Min Lee, Sarah J. Tabrizi, Michael Orth
Journal: Genome biology (2022)

Abstract Background A major challenge in neurodegenerative diseases concerns identifying biological disease signatures that track with disease progression or respond to an intervention. Several clinical trials in Huntington disease (HD), an inherited, progressive neurodegenerative disease, are currently ongoing. Therefore, we examine whether peripheral tissues can serve as a source of readily accessible biological signatures at the RNA and protein level in HD patients. Results We generate large, high-quality human datasets from skeletal muscle, skin and adipose tissue to probe molecular changes in human premanifest and early manifest HD patients—those most likely involved in clinical trials. The analysis of the transcriptomics and proteomics data shows robust, stage-dependent dysregulation. Gene ontology analysis confirms the involvement of inflammation and energy metabolism in peripheral HD pathogenesis. Furthermore, we observe changes in the homeostasis of extracellular vesicles, where we find consistent changes of genes and proteins involved in this process. In-depth single nucleotide polymorphism data across the HTT gene are derived from the generated primary cell lines. Conclusions Our ‘omics data document the involvement of inflammation, energy metabolism, and extracellular vesicle homeostasis. This demonstrates the potential to identify biological signatures from peripheral tissues in HD suitable as biomarkers in clinical trials. The generated data, complemented by the primary cell lines established from peripheral tissues, and a large panel of iPSC lines that can serve as human models of HD are a valuable and unique resource to advance the current understanding of molecular mechanisms driving HD pathogenesis.
Mutant Samd9l expression impairs hematopoiesis and induces bone marrow failure in mice
Authors: Sherif Abdelhamed, Melvin E. Thomas, Tamara Westover, Masayuki Umeda, Emily Xiong, Chandra Rolle, Michael P. Walsh, Huiyun Wu, Jason R. Schwartz, Virginia Valentine, Marcus Valentine, Stanley Pounds, Jing Ma, Laura J. Janke, Jeffery M. Klco
Journal: Journal of Clinical Investigation (2022)

SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here, we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-β as a potential targetable pathway. Further, we observed nonrandom genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.
The course of pain and dysphagia after radiofrequency ablation for Barrett’s esophagus-related neoplasia
Authors: Anouk Overwater, Sjoerd G. Elias, Erik J. Schoon, Jacques J. G. H. M. Bergman, Roos E. Pouw, Bas L. A. M. Weusten
Journal: Endoscopy (2022)

Background Radiofrequency ablation (RFA) is effective for eradication of Barrett’s esophagus (BE) neoplasia, but little is known on the course of pain and dysphagia after RFA. We aimed to describe the course of post-RFA symptoms and to identify possible associated risk factors. Methods In this multicenter, observational cohort study, all RFA procedures registered in a prospective database were included. Patient and treatment characteristics were collected from medical records and patients self-registered post-procedural symptoms in electronic symptom diaries for 14 days. Mixed model regression was used for the analyses. Results In total, 255 diaries were completed. Post-RFA pain was reported for 95 % (95 %CI 93–98) of procedures (median duration 14 days; 25th–75th percentiles [p25–p75] 11–14) and major pain for 64 % (95 %CI 58–69; median duration 8 days, p25–p75 3–13). Post-procedural pain significantly increased with BE length, younger age, and no prior ablation. Dysphagia was present after 83 % (95 %CI 79–88) of procedures (median duration 13 days, p25–p75 9–14). The risk of dysphagia decreased with age and increased when patients experienced more pain. Conclusions RFA treatment for BE-related neoplasia seems a significant burden for patients, and post-procedural symptoms should be taken into account when counseling patients before starting endoscopic eradication therapy.
Mental health care for older adults: recent advances and new directions in clinical practice and research
Authors: Charles F. Reynolds, Dilip V. Jeste, Perminder S. Sachdev, Dan G. Blazer
Journal: World Psychiatry (2022)

The world's population is aging, bringing about an ever-greater burden of mental disorders in older adults. Given multimorbidities, the mental health care of these people and their family caregivers is labor-intensive. At the same time, ageism is a big problem for older people, with and without mental disorders. Positive elements of aging, such as resilience, wisdom and prosocial behaviors, need to be highlighted and promoted, both to combat stigma and to help protect and improve mental health in older adults. The positive psychiatry of aging is not an oxymoron, but a scientific construct strongly informed by research evidence. We champion a broader concept of geriatric psychiatry - one that encompasses health as well as illness. In the present paper, we address these issues in the context of four disorders that are the greatest source of years lived with disability: neurocognitive disorders, major depression, schizophrenia, and substance use disorders. We emphasize the need for implementation of multidisciplinary team care, with comprehensive assessment, clinical management, intensive outreach, and coordination of mental, physical and social health services. We also underscore the need for further research into moderators and mediators of treatment response variability. Because optimal care of older adults with mental disorders is both patient-focused and family-centered, we call for further research into enhancing the well-being of family caregivers. To optimize both the safety and efficacy of pharmacotherapy, further attention to metabolic, cardiovascular and neurological tolerability is much needed, together with further development and testing of medications that reduce the risk for suicide. At the same time, we also address positive aging and normal cognitive aging, both as an antidote to ageism and as a catalyst for change in the way we think about aging per se and late-life mental disorders more specifically. It is in this context that we provide directions for future clinical care and research.
Real‐world evidence for the long‐term effect of allergen immunotherapy: Current status on database‐derived European studies
Authors: Christian Vogelberg, Ludger Klimek, Bernd Brüggenjürgen, Marek Jutel
Journal: Allergy (2022)

Randomized controlled trials (RCTs) are the gold-standard for benefit-risk assessments during drug approval processes. Real-word data (RWD) and the resulting real-world evidence (RWE) are becoming increasingly important for assessing the effectiveness of drug products after marketing authorization showing how RCT results are transferred into real life care. The effectiveness of allergen immunotherapy (AIT) has been assessed in several RWE studies based on large prescription databases. We performed a literature search for retrospective cohort assessments of prescription databases in Europe to provide an overview on the methodology, long-term effectiveness outcomes, and adherence to AIT. Thirteen respective publications were selected. AIT was more effective in reducing the progression of allergic rhinitis (AR) compared to a non-AIT control group receiving only symptomatic treatment for AR for up to 6 years. The development and progression of asthma were hampered for most endpoints in patients treated with most preparations compared to the non-AIT group, receiving only anti-asthmatic medication. The results for "time to onset" of asthma were inconsistent. Adherence to AIT decreased during the recommended 3-year treatment period, however, in most studies higher adherence to subcutaneous than to sublingual AIT was shown. The analysis of long-term effectiveness outcomes of the RWE studies based on prescription databases confirms the long-term efficacy of AIT demonstrated in RCTs. Progression of rhinitis and asthma symptoms as well as delayed onset of asthma triggered by different allergens, real life adherence to the treatment shows differences in particular application routes.
Limited evidence for blood eQTLs in human sexual dimorphism
Authors: Eleonora Porcu, Annique Claringbould, Antoine Weihs, Kaido Lepik, Tom G. Richardson, Uwe Völker, Federico A. Santoni, Alexander Teumer, Lude Franke, Alexandre Reymond, Zoltán Kutalik
Journal: Genome Medicine (2022)

Abstract Background The genetic underpinning of sexual dimorphism is very poorly understood. The prevalence of many diseases differs between men and women, which could be in part caused by sex-specific genetic effects. Nevertheless, only a few published genome-wide association studies (GWAS) were performed separately in each sex. The reported enrichment of expression quantitative trait loci (eQTLs) among GWAS-associated SNPs suggests a potential role of sex-specific eQTLs in the sex-specific genetic mechanism underlying complex traits. Methods To explore this scenario, we combined sex-specific whole blood RNA-seq eQTL data from 3447 European individuals included in BIOS Consortium and GWAS data from UK Biobank. Next, to test the presence of sex-biased causal effect of gene expression on complex traits, we performed sex-specific transcriptome-wide Mendelian randomization (TWMR) analyses on the two most sexually dimorphic traits, waist-to-hip ratio (WHR) and testosterone levels. Finally, we performed power analysis to calculate the GWAS sample size needed to observe sex-specific trait associations driven by sex-biased eQTLs. Results Among 9 million SNP-gene pairs showing sex-combined associations, we found 18 genes with significant sex-biased cis -eQTLs (FDR 5%). Our phenome-wide association study of the 18 top sex-biased eQTLs on &gt;700 traits unraveled that these eQTLs do not systematically translate into detectable sex-biased trait-associations. In addition, we observed that sex-specific causal effects of gene expression on complex traits are not driven by sex-specific eQTLs. Power analyses using real eQTL- and causal-effect sizes showed that millions of samples would be necessary to observe sex-biased trait associations that are fully driven by sex-biased cis -eQTLs. Compensatory effects may further hamper their detection. Conclusions Our results suggest that sex-specific eQTLs in whole blood do not translate to detectable sex-specific trait associations of complex diseases, and vice versa that the observed sex-specific trait associations cannot be explained by sex-specific eQTLs.
Author Correction: Wireless multilateral devices for optogenetic studies of individual and social behaviors
Authors: Yiyuan Yang, Mingzheng Wu, Abraham Vázquez-Guardado, Amy J. Wegener, Jose G. Grajales-Reyes, Yujun Deng, Taoyi Wang, Raudel Avila, Justin A. Moreno, Samuel Minkowicz, Vasin Dumrongprechachan, Jungyup Lee, Shuangyang Zhang, Alex A. Legaria, Yuhang Ma, Sunita Mehta, Daniel Franklin, Layne Hartman, Wubin Bai, Mengdi Han, Hangbo Zhao, Wei Lu, Yongjoon Yu, Xing Sheng, Anthony Banks, Xinge Yu, Zoe R. Donaldson, Robert W. Gereau, Cameron H. Good, Zhaoqian Xie, Yonggang Huang, Yevgenia Kozorovitskiy, John A. Rogers
Journal: Nature Neuroscience (2022)
Association Between SGLT2 Inhibitor Treatment and Diabetic Ketoacidosis and Mortality in People With Type 2 Diabetes Admitted to Hospital With COVID-19
Authors: Kamlesh Khunti, Yue Ruan, Jim Davies, Benjamin C.T. Field, Sophie Harris, Mikhail Kosiborod, Dinesh Nagi, Parth Narendran, Dipesh Patel, Robert E.J. Ryder, Kinga A. Várnai, Sarah H. Wild, Emma G. Wilmot, Rustam Rea, Rustam Rea, Emma Wilmot, Kamlesh Khunti, Sarah Wild, Ben Field, Parth Narendran, Rajiv Gandhi, Sophie Harris, Dinesh Nagi, Robert Ryder, Jim Davies, Steve Harris, Oliver Freeman, Ben Maylor, Kinga A. Várnai, Gail Roadknight, Melissa Cull, Yue Ruan, Amy Edwards, Susan Gelding, Kirun Gunganah, Pyei Aung, Moulinath Banerjee, Ali Chakera, Dominique Rouse, Syed Haris Ahmed, Ho Yee Cheung, Hywel Roberts, Susan Seal, Syed Saah Shah, Amir Hayat, Cynthia Mohandas, Htet Htet Aung, Su Khant Chel, Nyan Lin, Kavitia Narula, Furruq Quadri, Su Lei Yin, Yin Yin, Alamin Alkundi, Abdelmajid Musa, Emma Birbeck, Charles Bodmer, Irene Bossman, Sathis Kumar, Umesh Dashora, Elizabeth Toubi, Mansoor Zafar, Vinod Patel, Amitha Gopinath, Belinda Allan, Remat Karim, Dharshana Appuhamillage, Khubaib Ayoub, Charmaine Ilangaratne, Maliha Iqbal, Rory Maclean, Omar Mustafa, Susan Baxter, Malgorzata Adamus, Kevin Baynes, Siva Sivappriyan, Ryan D’Costa, Vernon Parfitt, Mazharul Islam, Sadia Nasir, Kinga Várnai, Senthil Vasan, Vilashini Arul Devah, Foteini Kavvoura, Lina Ficken, James Gilham, Vincent Simpson, Neil Walker, Umaira Aziz, Efthimia Karra, Dipesh Patel, Miranda Rosenthal, Tracy Curran, Angela Paisley, Parijat De P, Priscilla Sarkar, James Clark, Vesna Hogan, Lauren Jackson, Jamie-Leigh Williamson, R. Younes, Lucy Robin, Lydia Grixti, Suann Tee, Abilash Sathya, Mayank Patel, Catherine Holmes, Wasim Hanif, Sandip Ghosh, Ehtasham Ahmad, Ejaz Ahmed, Melanie Davies, Steven Hartshorn, Lee Simons, David Webb, Anupam Brahm, Seshadri Pramodh, Katy Frew, Alison Mackenzie, Abigail Wild, Helen Casey, Deborah Morrison, Conor McKeag, Anne Sillars, Angus Stirling, Fiona Smeeton, Syed Muhammad, Kofi Obuobie, Win Yin, Neera Agarwal, Mike Atkinson, Sai Ambati, Rahim Khan, Preethi Nalla, Arshiya Tabasum, Stamatios Zouras, Akhila Mallipedhi, Richard Chudleigh, David Williams
Journal: Diabetes Care (2022)

To determine the association between prescription of SGLT2 inhibitors (SGLT2is) and diabetic ketoacidosis (DKA) incidence or mortality in people with type 2 diabetes (T2D) hospitalized with COVID-19.